This phase II trial studies how well trametinib and v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor GSK2141795 work in treating patients with triple-negative breast cancer (breast cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 [HER2/neu] protein) that has spread to other places in the body. Trametinib and Akt inhibitor GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Objective response rate (ORR), defined as the proportion of patients who have had a partial response (PR) or complete response (CR) (RECIST 1.1 based) within the first 6 months after initiation of therapy with trametinib [ Time Frame: 6 months ] [ Designated as safety issue: No ]

The clinical benefit rate (CR+PR+SD) will be reported for patients after Part 1 and after Part 2.

Duration of objective response [ Time Frame: Date of documentation of response to the date of progression and/or death, assessed up to 52 weeks ] [ Designated as safety issue: No ]

The methods of Kaplan and Meier will be used to evaluate this.

Incidence of adverse events that are classified as either possibly, probably, or definitely related to study treatment graded by National Cancer Institute (NCI) CTCAE v4.0 [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: Yes ]

The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. All adverse event data that are graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment will be reviewed in the event of an actual relationship developing.

Overall survival (Part 2) [ Time Frame: Start date of the treatment to the date of the event (i.e., death) or the date of last follow-up to evaluate that event, assessed up to 52 weeks ] [ Designated as safety issue: No ]

The Kaplan-Meier method will be used to estimate overall survival distribution.

Progression-free survival [ Time Frame: The duration of time from start of treatment to time of progression or death, whichever comes first, assessed up to 52 weeks ] [ Designated as safety issue: No ]

The Kaplan-Meier method will be used to estimate progression-free survival distribution.

Proportion of patients who go off treatment due to adverse reactions [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: Yes ]

Proportion of patients who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: Yes ]

Tolerability of the regimen defined as the number of patients who required dose modifications and/or dose delays [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: Yes ]

Other Outcome Measures:

Predictive value of PTEN and other biomarkers on patient outcome (survival, ORR, and CBR) [ Time Frame: At time of disease progression, assessed up to 52 weeks ] [ Designated as safety issue: No ]

Ratios between tumors sampled prior to initiating trametinib single agent treatment and at time of progression (TOP) on either single agent trametinib or the combination (TOP/pre-treat ratio), will be calculated. These ratios will be median-centered and clustered using Cluster 2.0 software. Student's t-test for differences between average protein intensity ratios at these intervals will be calculated using Microsoft Excel by grouping all the ratios for individual clusters.

PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.

PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

I. To assess the anti-tumor activity associated with trametinib in combination with AKT inhibitor GSK2141795 after progression on trametinib in patients with metastatic TNBC.

II. To determine the progression-free survival following the initiation of treatment with trametinib monotherapy in patients with metastatic TNBC.

III. To determine the progression-free survival following the initiation of treatment with trametinib in combination with GSK2141795 in patients with metastatic TNBC.

IV. To determine the overall survival following the initiation of treatment with trametinib with GSK214179 in patients with metastatic TNBC.

V. To determine the nature and degree of toxicities associated with trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

VI. To determine the biomarker potential of phosphatase and tensin homolog (PTEN) to predict response to single agent trametinib.

VII. To determine molecular markers of sensitivity and resistance to trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

OUTLINE:

PART 1: Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.

PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 52 weeks.

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have histologically or cytologically confirmed metastatic invasive breast cancer that is negative for the estrogen receptor (ER), progesterone receptor (PR) and HER2 by institutional guidelines

Patients must have had exposure to at least 1 and no more than 3 prior chemotherapy regimens for the treatment of metastatic breast cancer

Patients must consent to both a pretreatment and a post-treatment mandatory research biopsy prior to enrolling on trial, and therefore, must have tissue (excluding bone or brain) that is amenable to biopsy

Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Life expectancy of greater than 3 months

Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) grade =< 1 (except alopecia) at the time of enrollment

Patients must be at least 4 weeks from last radiation dose; patients must be at least 4 weeks from last chemotherapy, targeted therapy, or biologic therapy (exception allowed for a 2 week washout for patients who were on chemotherapy at less than a standard of care dose, as long as all other eligibility criteria are met); patients must be at least 4 weeks from last surgical procedure and recovered from all post-operative complications

Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib monotherapy or in combination with GSK2141795 administration

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

History of another malignancy

Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible

History of interstitial lung disease or pneumonitis

History of type I diabetes mellitus; if a patient has type II diabetes, they must have a hemoglobin (hemoglobin A1C) =< 8%; patients with a screening fasting glucose > 120 mg/dL will be excluded

Uncontrolled hypothyroidism; patients must have a normal thyroid-stimulating hormone (TSH) per institutional standards at baseline

Patients who are receiving any other investigational agents

Individuals with symptomatic or progressive brain metastases are ineligible; subjects with treated brain metastases are eligible if they have no radiographic or other signs of progression in the brain for >= 3 weeks after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 3 weeks prior to study enrollment

History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib monotherapy or trametinib in combination with GSK2141795

Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on study treatment (megestrol if used as an appetite stimulant is allowed)

The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], gingko biloba, yohimbe, saw palmetto, or ginseng)

History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, history of hyperviscosity or hypercoagulability syndromes; visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm Hg

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01964924